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RUTH FAIR-MÄKELÄ: Lymphatic Endothelial Cells Regulate Traffic in Lymph Nodes Doctoral Dissertation, 180 Pp

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RUTH FAIR-MÄKELÄ: Lymphatic Endothelial Cells Regulate Traffic in Lymph Nodes Doctoral Dissertation, 180 Pp ANNALES UNIVERSITATIS TURKUENSIS UNIVERSITATIS ANNALES D 1507 D Ruth Fair-Mäkelä Ruth LYMPHATIC ENDOTHELIAL CELLS REGULATE TRAFFIC INTO LYMPH NODES Ruth Fair-Mäkelä Painosalama Oy, Turku, Finland 2020 Finland Turku, Oy, Painosalama ISBN 978-951-29-8175-5 (PRINT) – ISBN 978-951-29-8176-2 (PDF) TURUN YLIOPISTON JULKAISUJA ANNALES UNIVERSITATIS TURKUENSIS ISSN 0355-9483 (Print) SARJA - SER. D OSA - TOM. 1507 | MEDICA - ODONTOLOGICA | TURKU 2020 ISSN 2343-3213 (Online) LYMPHATIC ENDOTHELIAL CELLS REGULATE TRAFFIC IN LYMPH NODES Ruth Fair-Mäkelä TURUN YLIOPISTON JULKAISUJA – ANNALES UNIVERSITATIS TURKUENSIS SARJA - SER. D OSA – TOM. 1507 | MEDICA – ODONTOLOGICA | TURKU 2020 University of Turku Faculty of Medicine Institute of Biomedicine Medical Microbiology and Immunology Turku Doctoral Programme of Molecular Medicine Supervised by Academician Sirpa Jalkanen, MD, PhD Professor Masayuki Miyasaka, MD, PhD Medicity Research Laboratory Medicity Research Laboratory Medical Microbiology and Immunology Medical Microbiology and Immunology University of Turku University of Turku Turku, Finland Turku, Finland Adjunct Professor Kati Elima, MD, PhD Medicity Research Laboratory Medical Biochemistry and Genetics University of Turku Turku, Finland Reviewed by Professor Lena Claesson-Welsh, BD, PhD Adjunct Professor Marko Pesu, MD, PhD Rudbeck Laboratory and Science for Laboratory of Immunoregulation Life Laboratory Faculty of Medicine and Health Department of Immunology, Technology Genetics and Pathology Tampere University Uppsala University Tampere, Finland Uppsala, Sweden Opponent Professor Burkhard Ludewig, DVM, PhD Institute of Immunobiology Medical Research Center Kantonsspital St. Gallen St. Gallen, Switzerland The originality of this publication has been checked in accordance with the University of Turku quality assurance system using the Turnitin Originality Check service. Cover Image: A Lymph Node, Ruth Fair-Mäkelä ISBN 978-951-29-8175-5 (PRINT) ISBN 978-951-29-8176-2 (PDF) ISSN 0355-9483 (Print) ISSN 2343-3213 (Online) Painosalama Oy, Turku, Finland 2020 For Dad 3 UNIVERSITY OF TURKU Faculty of Medicine Institute of Biomedicine Medical Microbiology and Immunology RUTH FAIR-MÄKELÄ: Lymphatic endothelial cells regulate traffic in lymph nodes Doctoral Dissertation, 180 pp. Turku Doctoral Programme of Molecular Medicine October 2020 ABSTRACT Afferent lymphatic vessels transport leukocytes and soluble molecules from the periphery to lymph nodes. These vessels are lined with lymphatic endothelial cells (LEC), which are also present in lymph node sinuses. Lymph nodes are centers for the initiation of immune reactions, where antigen presenting cells present foreign antigens to naïve lymphocytes. Lymph-borne antigens are sorted based on their size in the subcapsular sinus (SCS) of the lymph node and only small antigens get direct access to the lymph node parenchyma. Lymphocytes migrate constantly into lymph nodes in search of foreign antigens. After searching for their cognate antigens, lymphocytes leave the nodes by egressing at the lymph node medullary sinus and the efferent lymphatics. LECs are known to regulate cell entry into lymph nodes as well as lymphocyte egress at the medullary sinus. The differences between the two populations of lymph node LECs, namely the afferent and efferent lymphatics, have not been thoroughly investigated. My doctoral studies describe two new molecules expressed in the afferent and efferent lymphatics (Msr1 and Robo4) and their role in lymphocyte migration. We also investigated how large antigens and antibodies get access into the lymph node parenchyma. Msr1 and Robo4 regulate lymphocyte migration and turnover in peripheral lymph nodes and Peyer’s patches. Moreover, we discovered that LECs transcytose large antigens and antibodies instantly into the lymph node parenchyma. These studies broaden the current view of LECs as regulators of cell and molecular trafficking at the lymph node sinuses. Our results also suggest that the effective delivery of lymph-borne antibodies into lymph nodes may be therapeutically harnessed. KEYWORDS: lymphatic endothelial cells, lymph node, lymphocyte migration, Msr1, Robo4, antibody transcytosis 4 TURUN YLIOPISTO Lääketieteellinen tiedekunta Biolääketieteen laitos Lääketieteellinen mikrobiologia ja immunologia RUTH FAIR-MÄKELÄ: Lymfaattiset endoteelisolut säätelevät imusolmukkeen liikennettä Väitöskirja, 180 s. Molekyylilääketieteen tohtoriohjelma Lokakuu 2020 TIIVISTELMÄ Imusuonet kuljettavat valkosoluja sekä liukoisia molekyylejä perifeerisistä kudoksista imusolmukkeisiin. Lymfaattiset endoteelisolut verhoavat sekä suonien että imusolmukkeen onteloiden sisäpintoja. Imusolmukkeet ovat tärkeitä keskuksia, joissa elimistön immuunireaktiot saavat alkunsa. Antigeenejä esittelevät valkosolut esittelevät vieraat molekyylit lymfosyyteille, mikä saa aikaan niiden aktivoitu- misen. Imunesteessä olevat antigeenit lajitellaan koon mukaan imusolmukkeen subkapsulaarisinuksessa ja vain pienillä molekyyleillä on pääsy imusolmukkeen sisäosiin. Lymfosyytit kiertävät jatkuvasti imusolmukkeissa etsien vieraita anti- geenejä ja poistuvat imusolmukkeesta medullaarisinuksen vieviä imusuonia pitkin. Lymfaattiset endoteelisolut säätelevät valkosolujen pääsyä imusolmukkeeseen sekä niiden pois lähtöä medullaarisinuksessa. Imusolmukkeessa olevien tuovien ja vievien endoteelisolujen eroja ei ole aikaisemmin kuvattu. Väitöskirjassani tutkin kahden uuden lymfaattisissa endoteelisoluissa ilmennettävän molekyylin (Msr1, Robo4) merkitystä valkosoluliikenteen säätelyssä. Selvitimme myös, miten suuret antigeenit sekä vasta-aineet pääsevät imusolmukkeen sisäosiin. Sekä Msr1 että Robo4 säätelevät lymfosyyttien kulkua niin perifeerisissä kuin suoliston pinnan imusolmukkeissa. Lymfaattiset endoteelisolut myös kuljettavat aktiivisesti suuria antigeenejä sekä vasta-aineita imusolmukkeen sisäosiin. Väitöskirjani tulokset laajentavat käsitystämme lymfaattisten endoteelisolujen merkityksestä imusolmuk- keen liikenteen säätelijöinä. Tutkimukseni tuloksia vasta-aineiden kulkemisesta imuteitä pitkin imusolmukkeisiin voidaan myös hyödyntää terapeuttisesti. AVAINSANAT: lymfaattiset endoteelisolut, imusolmuke, lymfosyyttiliikenne, Msr1, Robo4, vasta-aineiden transsytoosi 5 Table of Contents Abbreviations .................................................................................. 9 List of Original Publications ......................................................... 11 1 Introduction ........................................................................... 12 2 Review of the Literature ....................................................... 14 2.1 The lymphatic system ............................................................ 14 2.1.1 Early development of lymphatic vessels ...................... 14 2.1.2 Lymphatic vessel structure .......................................... 15 2.1.2.1 Lymphatic endothelial cells ........................... 16 2.1.3 Function of the lymphatic system ................................ 17 2.1.3.1 Regulation of fluid homeostasis .................... 17 2.1.3.2 Lipid absorption ............................................ 18 2.1.4 The lymphatic system in disease ................................. 19 2.1.4.1 Abnormal fluid homeostasis .......................... 19 2.1.4.2 Role in cancer ............................................... 19 2.2 The lymph node ..................................................................... 19 2.2.1 Lymph node organogenesis ........................................ 20 2.2.2 Lymph node structure.................................................. 21 2.2.2.1 Lymph node lymphatics ................................ 22 2.2.2.2 Lymph node blood vasculature ..................... 23 2.2.2.3 Reticular cells of the lymph node .................. 24 2.2.2.3.1 Fibroblastic reticular cells ............. 24 2.2.2.3.2 Follicular stromal cells .................. 25 2.2.2.4 Lymph node immune cells ............................ 26 2.2.2.4.1 Lymphocytes ................................ 26 2.2.2.4.2 Resident macrophages ................ 26 2.2.2.4.3 Dendritic cells ............................... 27 2.2.3 Function of the lymph node ......................................... 28 2.2.3.1 Transporting antigens ................................... 28 2.2.3.1.1 Role of the reticular conduit .......... 28 2.2.3.1.2 Large antigens ............................. 29 2.2.3.1.3 Infectious agents .......................... 30 2.2.3.2 Stromal cells regulate peripheral tolerance ... 30 2.3 Immune cell migration ............................................................ 31 2.3.1 Migration via afferent lymphatics ................................. 33 2.3.1.1 Intravasation into lymphatics ......................... 33 2.3.1.2 Migration through the SCS ............................ 34 2.3.2 Migration via the blood vasculature ............................. 35 6 2.3.3 Intranodal migration ..................................................... 37 2.3.4 Lymphocyte egress ..................................................... 38 2.4 Intestinal lymphocyte and antigen traffic ................................. 40 2.4.1 Transporting intestinal antigens ................................... 41 2.4.2 Immune cell migration in gut lymphoid tissues ............. 41 2.5 Inflammation induces changes in the lymph node .................. 42 3 Aims ....................................................................................... 44 4 Materials and Methods .......................................................... 45
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